mTOR/p70S6K in Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia.

Author disclosures are available with the text of this letter at www.atsjournals.org. Philip G. Bardin, Ph.D.

Kathy Low, M.B.B.S. Peter Holmes, M.B.B.S. Garun Hamilton, Ph.D.

Monash University and Medical Centre Melbourne, Australia

References

1. Christopher KL, Wood RP, Eckert CR, Blager FB, Raney RA, Souhrada JF. Vocal cord dysfunction presenting as asthma. N Engl J Med 1983; 308:1566–1570.

2. Low K, Lau KK, Holmes P, Crossett M, Vallance N, Phyland D, Hamza K, Hamilton G, Bardin PG. Abnormal vocal cord function in difficult-to-treat asthma. Am J Respir Crit Care Med 2011;184:50–56. 3. Braunstahl G-J. United airways concept. Proc Am Thorac Soc 2009;6:

652–654.

Copyrightª 2012 by the American Thoracic Society

mTOR/p70S6K in Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia

To the Editor:

We read with interest the review article by Nassar and coworkers (1) on diffuse idiopathic pulmonary neuroendocrine cell hyperpla-sia (DIPNECH). As correctly reported by the authors, this uncommon, possibly underrated, and often indolent disease may lead to severe respiratory obstructive symptoms and finally to death. In symptomatic patients, therapeutic options are limited to steroids, surgical lung resections, and lung transplantation.

Whatever the pathogenesis underlying the occurrence of DIPNECH, respiratory functions were deteriorated by a diffuse constrictive bronchiolitis secondary to fibrogenic peptides pro-duced by the proliferating neuroendocrine cells (2, 3).

Pulmonary and extrapulmonary neuroendocrine cell prolif-erations are characterized by a consistent expression of somato-statin receptors (SSR) (mainly types 2 and 5) and of mammalian target of rapamycin (mTOR) (4). These findings represent a solid scientific rationale in explaining the good clinical results recently reported with selective somatostatin analogs and mTOR inhibitors in neuroendocrine tumors (5). Little is known about the expression of SSR and mTOR in DIPNECH. Gorsh-tein and colleagues (6) recently highlighted the important role of SSR in DIPNECH showing a high uptake in all 11 cases tested by 111In-pentetreotide scintigraphy (Octreoscan) or gallium-68 (68Ga) 1,4,7,10-tetra-azacyclododecane-N,N9,N99, N999-tetraacetic acid-Tyr3-octreotide/Na3-octreotide 68 Ga-labeled 1,4,7,10-tetraazacyclododecane-N,N9,N,N9-tetraacetic acid positron emission/computed tomography imaging. In addi-tion, six patients with progressive respiratory symptoms treated with somatostatin analogs experienced disease stabilization with consistent improvement of respiratory functions in four cases.

To our knowledge, there are no data about mTOR-related mol-ecule expression in DIPNECH. By immunohistochemistry, we tested phosphorylated-mTOR (p-mTOR) and its major target, namely the ribosomal p70S6-kinase (p70S6K), in four cases of DIPNECH collected from our archival files. All these cases were characterized by the presence of a typical carcinoid and foci of neuroendocrine hyperplasia as well as tumorlets. On im-munohistochemistry, a robust and diffuse expression of p-mTOR and p70S6K was observed in all neuroendocrine lesions. Thus, the activation of mTOR pathway in DIPNECH seems to be en-tirely similar to what has been observed in sporadic carcinoid tumors (4).

Although preliminary, these results seem to support a scien-tific rationale in adopting mTOR inhibitors in DIPNECH and then to widen the spectrum of therapeutic tools in this intriguing disease.

Author disclosures are available with the text of this letter at www.atsjournals.org. Giulio Rossi, M.D.

Azienda Policlinico Modena, Italy

Alberto Cavazza, M.D. Arcispedale St. Maria Nuova Reggio Emilia, Italy

Paolo Graziano, M.D. San Camillo-Forlanini Hospital Roma, Italy

Mauro Papotti, M.D.

University of Torino at San Luigi Hospital Orbassano/Torino, Italy

References

1. Nassar AA, Jaroszewski DE, Helmers RA, Colby TV, Patel BM, Mookadam F. Diffuse idiopathic pulmonary neuroendocrine cell hy-perplasia: a systematic overview. Am J Respir Crit Care Med 2011; 184:8–16.

2. Aguayo SM, Miller YE, Waldron JA Jr, Bogin RM, Sunday ME, Staton GW Jr, Beam WR, King TE Jr. Brief report: idiopathic diffuse hyper-plasia of pulmonary neuroendocrine cells and airways disease. N Engl J Med 1992;327:1285–1288.

3. Davies SJ, Gosney JR, Hansell DM, Wells AU, du Bois RM, Burke MM, Sheppard MN, Nicholson AG. Diffuse idiopathic pulmonary neuro-endocrine cell hyperplasia: an under-recognized spectrum of disease. Thorax 2007;62:248–252.

4. Righi L, Volante M, Rapa I, Tavaglione V, Inzani F, Pelosi G, Papotti M. Mammalian target of rapamycin signaling activation patterns in neuroendocrine tumors of the lung. Endocr Relat Cancer 2010;17:977– 987.

5. Turaga KK, Kvols LK. Recent progress in the understanding, diagnosis, and treatment of gastroenteropancreatic neuroendocrine tumors. CA Cancer J Clin 2011;61:113–132.

6. Gorshtein A, Gross DJ, Barak D, Sternov Y, Refaeli Y, Shimon I, Grozinsky-Glasberg S. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia and the associated lung neuroendocrine tumors. Cancer (In press)

Copyrightª 2012 by the American Thoracic Society

From the Authors:

We appreciate the interest and comments by Dr. Rossi and col-leagues regarding our article (1). As with many diseases, aware-ness and recognition encourage progress in treatment. Recent publications and discussions within the past year have brought to the forefront treatment strategies in extrapulmonary neuroen-docrine tumors that may be relevant to pulmonary proliferations expressing somatostatin receptors (SSR) (2, 3). Although little is known about the expression of SSR and mammalian target of rapamycin (mTOR) in DIPNECH, the information highlighted by Gorshtein, Righi, and colleagues (4, 5) complements our clin-ical paper and illustrates the need to better understand the im-portant role of somatostatin analogs (SSA) and their potential for treatment in DIPNECH. Neuroendocrine cell proliferation with somatostatin receptor expression is the fundamental pathologic response to probable injury, so it makes teleological sense that SSA may be beneficial in the therapeutic paradigm.

The discussion of immunohistochemistry evidence, including the activation of the mTOR pathway in DIPNECH, is an

excellent example of the progress that can be made with recog-nition and international collaboration on this disease. These leads may result in successful treatment strategies utilizing mTOR inhibitors in DIPNECH.

Another point of importance is the role of octreotide analog radio-labeled nuclear scintigraphy with positron emission/ computed tomography imaging (6) in perhaps guiding treatment where the density of SSR in DIPNECH patients may predict therapeutic success with SSA.

As with most uncommon and often unrecognized diseases, collaboration may be the only way to obtain the volume of patients required to properly strategize and assess treatments. True progress and treatment algorithms would be best served with the establishment of an international registry for patients, a tissue repository, and the synergy of knowledge and experience between institutions.

Author disclosures are available with the text of this letter at www.atsjournals.org. D. E. Jaroszewski, M.D., M.B.A. F. Mookadam, M.B., B.Ch., M.Sc. Mayo Clinic Arizona

Scottsdale, Arizona A. A. Nassar, M.D.

University of California San Diego San Diego, California

References

1. Nassar AA, Jaroszewski DE, Helmers RA, Colby TV, Patel BM, Mookadam F. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: a systematic overview. Am J Respir Crit Care Med 2011; 184:8–16.

2. Turaga KK, Kvols LK. Recent progress in the understanding, diagnosis, and treatment of gastroenteropancreatic neuroendocrine tumors. CA Cancer J Clin 2011;61:113–132.

3. Cameron CM, Roberts F, Connell J, Sproule MW. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: an unusual cause of cy-clical ectopic adrenocorticotrophic syndrome. Br J Radiol 2011;84: e14–e17.

4. Gorshtein A, Gross DJ, Barak D, Strenov Y, Refaeli Y, Shimon I, Grozinksky-Glasberg S. Diffuse idiopathic pulmonary neuroendo-crine cell hyperplasia and the associated lung neuroendoneuroendo-crine tumors. Cancer (In press)

5. Righi L, Volante M, Rapa I, Tavaglione V, Inzani F, Pelosi G, Papotti M. Mammalian target of rapamycin signaling activation patterns in neuroendocrine tumors of the lung. Endocr Relat Cancer 2010;17:977– 987.

Copyrightª 2012 by the American Thoracic Society

Camphor, an Old Cough Remedy with a New Mechanism

To the Editor:

In an interesting correspondence, Patberg and colleagues (1) have commented on a recent proposal by Birring (2) on unex-plained chronic cough (UCC). The hypothesis regards the role of the transient receptor potential vanilloid (TRPV)1 channel as a common final pathway underlying the heightened cough sen-sitivity of individuals with UCC. The presence of TRPV1 in vagal afferents, the successful use of the selective TRPV1 stim-ulant, capsaicin, as a protussive agent in experimental animals and humans, and the lower threshold to capsaicin-induced

cough in patients with UCC have suggested (and Dr. Birring has reconsidered this hypothesis) a central role for TRPV1 hyperexpression and hyperfunction in chronic cough. Patberg and coworkers (1) further supported this hypothesis with the observation that an old cough remedy, camphorated oil, con-tains camphor, which initially stimulates but then strongly desensitizes TRPV1. Clinical evidence for the antitussive action of camphor has been also reported in their comment (1). We agree with the proposed hypothesis and with the implied ther-apeutic perspectives for TRPV1 desensitizers/antagonists. How-ever, camphor can no longer be regarded as a selective agent for TRPV1. Rather, camphor has been identified as a TRPA1 (“A” stands for ankyrin) channel antagonist. TRPA1 is coexpressed with TRPV1 in nociceptive neurons, including vagal afferents; various TRPA1 agonists, including cinnamaldehyde and acro-lein, cause cough by TRPA1 stimulation in guinea pigs (3) and humans (4); and camphor reduces TRPA1-mediated cough (3). Also, menthol (mentioned in the comment by Patberg and col-leagues) (1), an agonist of the cold receptor TRPM8 (and via this mechanism responsible for the fresh sensation associated with mint), and traditionally used as a cough remedy, has been found to inhibit TRPA1 (5). Thus, while we recognize the pos-sible role of TRPV1 in the mechanism of UCC, we recommend that the emerging role of TRPA1 not be disregarded. This is of particular relevance when considering the peculiar chemical features of TRPA1, which are responsible for the unique ability of this channel to sense a series of irritant and reactive endog-enous (associated with inflammation and tissue injury) and ex-ogenous (associated with environmental pollution) molecules, derived from oxidative and nitrative stress (6). Following the advice of the children’s song “John Brown’s baby had a cough,” the future challenge in drug discovery for the treatment of chronic cough would be better suited by a compound that more efficiently and safely combines the blocking property of cam-phor at both TRPV1 and TRPA1.

Author disclosures are available with the text of this letter at www.atsjournals.org. Pierangelo Geppetti, M.D. Silvia Benemei, M.D. University of Florence Florence, Italy Riccardo Patacchini, Ph.D. Chiesi Pharmaceuticals Parma, Italy References

1. Patberg KW, de Groot JR, Patberg Y. “John Brown’s baby had a cough”: a central role for TRPV1? [letter]. Am J Respir Crit Care Med 2011;184:382.

2. Birring SS. Controversies in the evaluation and management of chronic cough. Am J Respir Crit Care Med 2011;183:708–715.

3. Andre E, Gatti R, Trevisani M, Preti D, Baraldi PG, Patacchini R, Geppetti P. Transient receptor potential ankyrin receptor 1 is a novel target for pro-tussive agents. Br J Pharmacol 2009;158:1621–1628. 4. Birrell MA, Belvisi MG, Grace M, Sadofsky L, Faruqi S, Hele DJ, Maher

SA, Freund-Michel V, Morice AH. TRPA1 agonists evoke coughing in guinea pig and human volunteers. Am J Respir Crit Care Med 2009;180: 1042–1047.

5. Karashima Y, Damann N, Prenen J, Talavera K, Segal A, Voets T, Nilius B. Bimodal action of menthol on the transient receptor potential channel TRPA1. J Neurosci 2007;27:9874–9884.

6. Bessac BF, Sivula M, von Hehn CA, Escalera J, Cohn L, Jordt SE. TRPA1 is a major oxidant sensor in murine airway sensory neurons. J Clin Invest 2008;118:1899–1910.

Copyrightª 2012 by the American Thoracic Society Author Contributions: All authors have substantially contributed to the drafting

and revision of the letter and have approved the version to be published.